tbuckley/cabot-search huggingface dataset:
NCOG-02. MANAGEMENT OF PATIENTS WITH MELANOMA BRAIN METASTASES AND PRIOR SYSTEMIC TREATMENT EXPOSURE: A SINGLE-CENTER EXPERIENCE
Authors: Thiago P Muniz, Paola A Jablonska, Samuel D Saibil, Anna Spreafico, David Hogg, David Shultz, Marcus O Butler
Journal: Neuro-Oncology (2023)

Abstract Although systemic therapy (ST) for melanoma patients with untreated brain metastases (BrM) has activity, ST options for patients with melanoma BrM that develop on or after ST are limited. In this single-center retrospective study, we describe the characteristics and survival outcomes of patients aged &amp;gt; 18 years with metastatic melanoma and who developed BrM &amp;gt; 90 days after their first dose of checkpoint inhibitor (CPI) or targeted therapy (TT). Relevant clinical data and data on ST prior to and after BrM diagnosis were collected. MRIs were reviewed to assess intracranial progression-free survival (IC-PFS) as per RANO-BM criteria. The primary outcome was overall survival (OS). Cox regression model was applied to identify factors associated with OS. Between 2010 and 2019, we identified 103 patients with median age 56 (29-92) years, 69 (67%) of whom were male; 57 (55%) had BRAF V600-mutant tumors. Ninety-four (91%) had no known BrM at the time of first-line therapy. Median number of BrM was 3 (1-58), median number of prior ST was 1 (1-5), 75 (73%) had prior CPI exposure and 70 (68%) were on concurrent CPI or TT at the time of BrM diagnosis. Local treatments included SRS in 43 (42%) and WBRT in 46 (44%) patients. From BrM diagnosis, median IC-PFS and OS were 3.5 (95% CI 2.6-4.3) and 6.9 (95% CI 5.2-8.6) months, respectively. Adverse prognostic factors were: BRAF wild-type (HR 2.04, 95% CI 1.15-3.64), ECOG 2-4 (HR 3.55, 95% CI 1.93-6.53), and increasing number of prior ST (HR 1.62, 95% CI 1.23-2.13). CPI therapy that was continued, started, or restarted after BrM was associated with improved median OS compared to non-ICI therapy (9.9 vs. 3.5 months, HR 0.45, 95% CI 0.27-0.74). In conclusion, our data support development of CPI-based trials for patients who experience progression with BrM on or after modern ST.
NIMG-77. EARLY DIAGNOSIS OF NEUROCUTANEOUS MELANOSIS MASQUERADING AS SUBARACHNOID HEMORRHAGE
Authors: Hsien-Chung Chen, Shun-Tai Yang
Journal: Neuro-Oncology (2023)

Abstract A 50-year-old male presented to the emergency room with a sudden onset right upper limb facial numbness and dysphasia, soon followed by full-recovery. Brain computed tomography revealed hyperdense lesions within the left frontal sulcus, highly suspicious of subarachnoid hemorrhage. T1-weighted magnetic resonance imaging showed multiple leptomeningeal enhancement in the left frontal area.The digital subtraction angiography indicated an absence of vascular lesions. One-month after, the lesions progressed in the occipital area, when left sixth nerve palsy developed. Multiple giant nevus over the legs, trunk, and scalp had attracted attention. Owing to the suspicious symptomatic leptomeningeal lesions, open biopsy was performed. Surprisingly, diffuse, thick, black-colored tissue infiltration of the subarachnoid space, involving prominent cortical vessels, was noted. Pathology confirmed meningeal melanocytosis. Neurocutaneous melanosis is characterized by giant congenital or multiple satellite nevi and melanocytic tumors of the leptomeninges. Early disease diagnosis is crucial. Once the patient develops neurological symptoms, prognosis could quickly worsen.
NCOG-35. WEIGHING BENEFITS OF IMPROVED LONG TERM SURVIVAL AGAINST THE EFFECTS OF POST-RADIOTHERAPY NEUROCOGNITIVE DECLINE: ROLE OF RADIOTHERAPY FOR TREATMENT OF PEDIATRIC PRIMARY CNS NEOPLASMS
Authors: Nolan Brown, Cathleen Kuo, Oanh Nguyen, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE To comprehensively review and weigh benefits of radiotherapy for pediatric primary central nervous system (CNS) tumors, which lengthens survival in the setting of potentially debilitating morbidity, including post-radiotherapy neurocognitive decline. METHODS In this review, the authors examined all the published literature analyzing results of clinical trials, case series, and technical notes on patients undergoing radiotherapy for the treatment of tumors of the central nervous system, with an emphasis on neurocognitive decline and survival outcomes. RESULTS Radiotherapy is an essential component of the treatment regimen for pediatric medulloblastoma. A recent trial demonstrated association between contemporary treatment protocols and significant post-radiotherapy neurotoxicity. A new protocol for WNT 2-driven medulloblastoma has been proposed and is undergoing testing: 18 Gy in 10 fractions plus a tumor-bed boost of 36 Gy in 20 fractions for a total primary site dose of 54 Gy in 30 fractions without concurrent chemotherapy followed by the standard six cycles of adjuvant systemic chemotherapy. Maximal surgical resection remains the mainstay of therapy for low grade glioma, as radiation therapy is reserved for subsequent recurrence or progression. Management paradigms are similar for high grade gliomas and ependymomas. Overall, radiotherapy allows for greater lifetime survival but also lengthens the morbidity from late effects, especially neurocognitive decline. This is largely due to the unintended consequence of radiation- induced damage to the normal neural tissue caught in the beam trajectory. Advancements in photon-based radiotherapy confined the volume of the brain that was irradiated to fit the tumor margins more closely; however, the advent of PBRT further allows for greater sparing of normal neuronal tissue, by maximizing energy deposition at the tumor location while minimizing energy deposition both proximal and distal to the tumor target. CONCLUSION Future research is needed to develop interventions for those already suffering from the late effects of post-radiotherapy neurocognitive decline.
NCOG-36. IMPACT OF COLLAGEN TILE BRACHYTHERAPY AS TREATMENT FOR RECURRENT GLIOBLASTOMAS ON FUNCTIONAL STATUS AND QUALITY OF LIFE
Authors: Michael Garcia, David Brachman, Stuart Lee, Matthew Sean Peach, John Wanebo, Kris Smith, Clark Chen, Rupesh Kotecha, Manmeet Ahluwalia, Simon Hanft, Adam Nowlan, David McCracken, John Floyd, Mitesh Shah, Angela Richardson, Toral Patel, Huong Pham, Robert Ryan, Andrea Wasilewski, Colette Shen, Adam Robin, Tulika Ranjan, Kimberly Bojanowski-Hoang, Vincent DiNapoli, Roukoz Chamoun, Ondrej Choutka, Catherine Mercado, Devon Haydon, Lewis Leng, Analiz Rodriguez, Nimisha Deb, Akash Patel, David Piccioni, Lisa Campbell, Sita Patel, Angela Hall
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Recurrent glioblastoma is an aggressive disease with dismal prognosis despite advances in standard therapy, making the maintenance of functional status and quality of life (QOL) in patients an important endpoint during treatment. Here, we report functional status (KPS) and QOL metrics (LASA and FACT-Br) at 6-months post-treatment for recurrent glioblastoma patients treated with maximal safe resection followed by intraoperative placement of collagen tile brachytherapy with Cesium-131 (Surgically Targeted Radiation Therapy or STaRT), a novel brachytherapy carrier. OBJECTIVE To assess the impact of STaRT on KPS and QOL among patients with recurrent glioblastoma (rGBM) at 6-months post-treatment. METHODS Patients were treated between 10/2020 and 05/2023 as part of a multi-institutional registry study (NCT#04427384). KPS was used to measure functional status. Linear Analog Self-Assessment (LASA) and Functional Assessment of Cancer Therapy – Brain (FACT-Br) were used to measure QOL. All assessments were collected at pre-surgery, and 1,3, and 6-months post-treatment. RESULTS 57 rGBM patients were treated on the Registry between 10/2020 and 05/2023. Of the 57 participants, 47 participants remain in the study, with 21 participants reaching the 6-month time point (5 exits, 5 deaths). Median age was 60 years (range 28-81). Methylguanine methyltransferase (MGMT) promoter was methylated in 17.5%, unmethylated in 38.5%, and unknown in 44%. Gross total resection was achieved in 72% of participants. Median KPS was 80% (range 40%-100%) at screening versus 70% (range 40%-90%) at 6 months post-treatment. Median LASA was 37 (range 8-50) at pre-surgery versus 34 (range 5-48) at 6-months post-treatment. Minimally important differences (MID) were noted between pre-surgery (136.9 ± 29.5) and 6-months post-treatment (112.5 ± 35.7) for the FACT-Br Total Score. CONCLUSION This interim data analysis supports further investigation of STaRT as a treatment for recurrent glioblastomas as a means of providing stable functional status and quality of life.
EXTH-35. UNRAVELING THE MECHANISTIC UNDERPINNINGS OF MRNA VACCINE MEDIATED INNATE IMMUNE ACTIVATION AND LYMPHOCYTE TRAFFICKING FOR HIGH-GRADE GLIOMAS
Authors: Anna DeVries, Hector Mendez-Gomez, Jonathan Chardon-Robles, Nagheme Thomas, James McGuiness, Sheila Carrera-Justiz, Paul Castillo, Frances Weidert, Duane Mitchell, Elias Sayour
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND High-grade gliomas are an aggressive subset of CNS tumors in need of novel treatment strategies. However, tumor heterogeneity, the immunosuppressive tumor microenvironment (TME) and the lack of immunogenic tumor specific targets have limited the translational power of many immunotherapies for high-grade gliomas. The promising application of mRNA vaccines has the potential to restore immunosurveillance through peripheral and intratumoral reprograming of the TME. METHODS Our lab has developed a lipid particle multilamellar aggregate (RNA-LPA) vaccine that encapsulates tumor specific RNA and delivers the payload to the immune system in a highly immunogenic fashion, similar to that of a virus. We sought to assess anti-tumor activity across preclinical murine models and investigate the mechanisms for response. RESULTS We demonstrated the immune activation potential of RNA-LPAs encoding for glioma associated antigens (i.e., pp65 and H3K27M) in preclinical murine models. We also showed activity of personalized RNA-LPA in canine and human studies (NCT04573140) for patients with high-grade gliomas. Exogenous RNA is recognized by pathogen recognition receptors (PRRs) which trigger a type I interferon (IFN) response and proinflammatory cytokine production. While most RNA based vaccines activate an innate immune response primarily through toll-like receptor 7 (TLR7), we reveal that RNA-LPAs activate the innate immune system through retinoic acid-inducible gene 1 protein (RIG-I). As a result of PRR signaling, the type I IFN and cytokine/chemokine response (IL-6, G-CSF, TNF-alpha, CXCL9, CXCL10, CCL2, CCL4) mediates massive recruitment of activated dendritic cell and activated T cell in lymphoreticular organs where antigen presenting cells and cytolytic T cell colocalize to initiate an adaptive immune response against glioma specific antigens. CONCLUSION RNA-LPAs are a novel platform immunotherapy that initiate anti-tumor immunity against malignant brain tumors through noncanonical activation of intracellular PRRs and widespread recruitment of peripheral blood mononuclear cells to sites of RNA-LPA localization.
EXTH-29. INTERNEURONS THAT BITE, A CELLULAR THERAPY FOR HIGH GRADE GLIOMA
Authors: Stephanie Brosius, William Manley, Stewart Anderson, Thomas De Raedt
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma has a poor prognosis with limited therapeutic options. Cellular therapies, like CAR-T therapy, have unfortunately shown limited efficacy for brain tumors, due to the lack of unique tumor antigens, the downregulation of targeted antigens, and the immune suppressive tumor microenvironment (TME). To circumvent these brain tumor specific obstacles, we developed a cellular immunotherapy delivery system, derived from post-mitotic Migratory Cortical Inhibitory Interneuron Precursors (MCIPs), that induces a cytotoxic tumor response in glioblastoma independent of unique tumor antigens. During fetal brain development, MCIPs are chemoattracted to migrate long distances from their subcortical origins into the cerebral cortex. The MCIP chemoattractant CXCL12 activates CXCR4 to induce this migration. Intriguingly, CXCL12 is secreted by glioblastoma, suggesting they chemoattract MCIPs. Excitingly, our in vitro and in vivo data indeed show that MCIPs robustly migrate to the majority of glioblastoma cell lines evaluated. Crucially, this migration is independent of unique tumor antigens and the TME and provides us with the opportunity to use MCIPs as a delivery vector for cytotoxic agents. In one approach, we successfully eliminated EGFR expressing glioblastoma in vivo by modifying MCIPs to secrete EGFR Bispecific T-cell Engagers (BiTE). BiTE engagement with a tumor cell results in T-cell activation and elimination of the engaged tumor cell. Importantly, the T-cells have no innate recognition of the tumor cell, this is provided by the BiTE. Local EGFR BiTE secretion has limited systemic toxicity, thereby making EGFR a viable non-unique target. MCIPs can be equipped with a range of agents that eliminate glioblastoma. As a therapy, we envisage injecting modified MCIPs, differentiated from patient or donor “off the shelf” induced pluripotent stem cells, into the margin of the surgical cavity to “clean-up” tumor cells remaining post-surgery. An interneuron clinical trial for epilepsy (NCT05135091) is ongoing, highlighting the translational potential of our MCIP cellular therapy.
EXTH-30. GOLD NANOSTARS OBVIATE LIMITATIONS TO LASER INTERSTITIAL THERMAL THERAPY (LITT) AND ENHANCE THE POST-LITT IMMUNE RESPONSE
Authors: Ethan Srinivasan, Yang Liu, Ren Odion, Pakawat Chongsathidkiet, Lucas Wachsmuth, Aden Haskell-Mendoza, Ryan Edwards, Aidan Canning, Gavin Willoughby, Joseph Hinton, Stephen Norton, Christopher Lascola, Paolo Maccarini, Christopher Mariani, Tuan Vo-Dinh, Peter Fecci
Journal: Neuro-Oncology (2023)

Abstract Laser interstitial thermal therapy (LITT) is a minimally-invasive technique for the treatment of intracranial tumors that uses a stereotactically-guided laser and real-time magnetic resonance imaging (MRI) to monitor ablation progress. Previous applications of gold nanostars (GNS) in laser ablation of tumors have studied extracranial tumors only and utilized externally administered near infrared radiation that cannot penetrate the cranial compartment. Herein, we present a novel platform for employing GNS in intracranial tumors. We developed non-toxic GNS that exhibit maximum photothermal effects at the 1064 nm laser wavelength used in the FDA-approved clinical Neuroblate® LITT system. Monte Carlo simulations demonstrate that our GNS can accelerate and focus thermal energy distributions. Using ex vivo tumor phantom models, we found that GNS-infused phantoms demonstrate more rapid heating and improved spatial conformation of thermal energy, with neighboring material exposed to lower temperatures than controls. In our intracranial CT-2A glioma model, we quantified accumulation of radiolabeled GNS in tumor tissue via PET/CT. As further validation of tumor-selective GNS accumulation, we used two-photon luminescence to show that GNS selectively accumulate and are retained in intracranial tumors at 24 and 72 hours post-injection. We then utilized our in vivo heterotopic CT-2A model to assess the capacity of systemically-delivered GNS to augment laser ablation; we were able to achieve higher ablation temperatures and more efficient temperature ramping with LITT+GNS. Finally, we explored the potential of LITT+GNS to synergize with immunotherapy to further enhance the post-ablation immune response and found that combination therapy resulted in improved tumor control and immunologic memory that was protective against tumor rechallenge. These results support the ability of GNS to optimize LITT for the treatment of intracranial tumors by improving efficiency and safety, and illustrate the potential of this platform to synergize with immunotherapy.
NCOG-34. BRAIN PET IMAGING OF PAIRED HELICAL FILAMENT TAU IN OLDER ADULTS WITH CANCER: PILOT STUDY TO IDENTIFY MECHANISMS OF COGNITIVE IMPAIRMENT AFTER CANCER THERAPY
Authors: Michael Parsons, Liesel Von Imhof, Ryan Eckbo, Yuta Katsumi, Alexandra Touroutoglou, Isabel Arrillaga-Romany, Bradford Dickerson, Jorg Dietrich
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Cancer-related cognitive impairment (CRCI) occurs in up to 75% of patients treated with chemotherapy for systemic cancer, and older patients treated for CNS cancer receiving brain radiation therapy (RT) and chemotherapy are particularly at risk. The mechanisms of injury and CRCI remain unknown. In neurodegenerative disorders, deposition of paired helical filament tau (PHFTau) is correlated with nature and extent of cognitive symptoms. The role of PHFTau in CRCI has not been elucidated. We conducted a pilot study to determine whether CRCI is associated with PHFTau. METHODS Patients (age &amp;gt;60) diagnosed with mild cognitive impairment (MCI) or dementia after chemotherapy and/or brain RT underwent Tau PET imaging using [F18]Flourtaucipir. Cortical [F18]Flourtaucipir binding was quantified by standard uptake value ratio (SUVR) in 68 regions of interest (ROIs) and compared to a control group (n=22). SUVR in each ROI for each subject was considered significantly elevated when it was &amp;gt;2SD above the control group (p&amp;lt; 0.05). Neuropsychological test scores were correlated with PHFTau distribution. RESULTS Five patients with MCI/Dementia following cancer therapy participated. Two patients with prior chemo-RT for CNS cancer and prominent executive dysfunction had no significant F[18]T807 uptake. However, three patients treated with systemic chemotherapy for non-CNS cancer and neuropsychological profiles dominated by episodic memory impairment showed F[18]T807 uptake in patterns typical of AD dementia in temporal, parietal and cingulate ROI’s (n=2), or uptake in the entorhinal and inferior temporal ROIs (n=1). DISCUSSION In this pilot study, [F18]Flourtaucipir imaging of patients with cancer and MCI/Dementia showed that executive dysfunction after RT was not associated with abnormal PHFTau whereas amnestic declines after chemotherapy were associated with PHFTau in medial temporal lobes and beyond. Given the cross-sectional study, timing of tau accumulation in relation to cancer/treatment is unknown. Prospective studies are needed to understand the relevance of PHFTau in CRCI.
CTIM-36. IMMUNOHISTOCHEMISTRY EVALUATION ON PRE-TREATMENT TUMOR TISSUE PREDICTS TREATMENT RESPONSE TO MN-166 (IBUDILAST) AND TEMOZOLOMIDE COMBINATION THERAPY IN GLIOBLASTOMA PATIENTS
Authors: Justin Lathia, Adam Lauko, Kazuko Matsuda, Malath Makhay, Lakshmi Nayak, Ugonma Chukwueke, Eudocia Lee, David Reardon, Rameen Beroukhim, Tracy Batchelor, Elisa Aquilanti, Patrick Wen
Journal: Neuro-Oncology (2023)

Abstract STUDY DESIGN MN-166-GBM-1201 is a Phase I/II open-label clinical trial to evaluate MN166 (ibudilast) and temozolomide (TMZ) combination treatment in newly diagnosed and recurrent glioblastoma (GBM) patients. 62 GBM patients (34 newly diagnosed and 28 recurrent) were enrolled in the study. All patients received MN-166 and TMZ combination treatment until disease progression or withdrawal from the study for other reasons. METHODS Pre-treatment tumor tissue at initial surgery from 24 study participants was evaluated to determine potential predictors of response to MN-166, which has been shown to inhibit the interaction between macrophage migration inhibitory factor (MIF) and CD74 with ERK phosphorylation downstream of CD74. We looked at CD11b and CD3 expression to characterize the immune profile within the tumors and Ki67 to determine percentage of proliferating tumor cells, all of which were calculated by a masked researcher. Then, patients were stratified based on progression within the first five months after receiving MN-166 and TMZ. RESULTS Patients who did not progress within 5 months had a significantly lower percentage of CD3+ T cell infiltration than nonresponding patients (p = 0.045), and CD74 expression was lower in patients with no progression (p = 0.16). The other markers demonstrated no differences. MN-166 and TMZ combination therapy was generally safe and well tolerated. CONCLUSION CD3 expression was a good predictor for tumor progression for five months in recurrent GBM patients treated with MN-166 and TMZ. T cell infiltration within GBM tumors has been an active area of research with the success of immune checkpoint blockade (ICB) therapies in other cancers. Moreover, MN-166 has been shown to impact immune suppressive myeloid cells, which are linked to the immune suppressive tumor microenvironment and a resistance mechanism to ICB. Collectively, we postulate that the efficacy of MN-166 for treatment of GBM could be further enhanced by co-treatment with ICBs.
INNV-17. TREATMENT DECISION AND QUALITY OF LIFE OF PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA RECEIVING TUMOR TREATING FIELDS (TTFIELDS) THERAPY IN ROUTINE CLINICAL CARE: RESULTS FROM THE TIGER STUDY
Authors: Oliver Bähr, Ghazaleh Tabatabai, Rainer Fietkau, Roland Goldbrunner, Martin Glas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND TTFields therapy, concurrent with temozolomide, is approved for treatment of newly diagnosed glioblastoma (ndGBM), following results from the pivotal EF-14 study. The multicenter, prospective TIGER study (NCT03258021) investigated real-world use of TTFields therapy in patients with ndGBM during routine clinical care in Germany. Data on patient treatment decisions and health-related quality of life (HRQoL) are reported. METHODS Reasons for patient decision to receive TTFields therapy were evaluated via questionnaire (scoring scale: 1 [not at all] to 5 [strongly]) at baseline. In patients who decided to receive TTFields therapy, HRQoL was assessed via the EORTCQLQC30/BN20 questionnaire at baseline, and 2 and 4 months after initiating therapy. HRQoL parameters included: global health status and functioning, insomnia, headaches, fatigue, nausea/vomiting, pain, itchy skin, hair loss, seizures, dyspnea, appetite loss, constipation, diarrhea, visual disorder, leg weakness, drowsiness, bladder control, motor dysfunction, communication deficit, future uncertainty, and financial difficulties. RESULTS Overall, 710 patients (259 female; 451 male) were enrolled (Aug 2017–Nov 2019). Mean age was 59 years (range: 19–85). In total, 582 (82%) patients decided to start TTFields therapy, while 128 (18%) declined; the proportion of women was similar in each group (36% and 38%, respectively). Predominant reasons for deciding to start TTFields therapy were the prospect of treatment success (mean score: 4.5) and doing something to fight their disease (4.2). Predominant reason for deciding against TTFields therapy was carrying the device (4.4). During 4-month study follow-up, there was no decline or improvement in any HRQoL parameter, except for more itchy skin, consistent with EF-14 data. CONCLUSION TIGER is the largest non-interventional study to date on TTFields therapy use in routine clinical care. Most patients opted to receive TTFields therapy, with fighting their disease and hope for treatment success as major motivators. HRQoL was not impaired during follow-up, except for skin itchiness.